Great progress has been made treating psoriasis over the last 10 years, predominantly using T cell-targeted therapies. However, dendritic cells (DCs) offer an even more attractive target to prevent psoriasis and other auto-inflammatory diseases. DCs represent a choke point in the evolution chronic inflammation by driving pathogenic Th1/17 cell responses. We have previously dissected the DC-T-cell axis in psoriasis, but now there is a significant opportunity to understand the role and function of more proximal DCs. Our group first described a population of Inflammatory myeloid DCs, which are as abundant as T cells in psoriasis skin lesions. These inflammatory DCs are reduced with every treatment for psoriasis we have examined, but not decreased if the treatment did not clear the psoriasis. Inhibiting DCs at this bottleneck will enable us to prevent inflammatory lesion development in the skin and debilitating chronic inflammatory organ diseases, as well as treat existing lesions. Our central hypothesis is that circulating CD16+ monocytes are recruited into skin, becoming activated by the local environment to develop into inflammatory DCs. These monocytes migrate into the skin due to the chemotactic gradient of CX3CL1/fractalkine, and anti-microbial peptides are candidates in the local environment that can activate the monocytes. There are many examples of monocytes becoming inflammatory DCs and macrophages in murine models, including colitis, infections, atherosclerosis, and myocarditis. Although much less in known in humans, circulating CD16+ monocytes are elevated in psoriasis and other many other conditions, including sepsis, rheumatoid arthritis, HIV infection, and coronary artery disease. The experiments in this proposal will directly enhance our knowledge of monocyte populations and the DCs and macrophages they give rise to, and support the development of new treatment protocols that target these cells in psoriasis and other autommmune diseases. The current approach to treating skin diseases with a critical pathogenic T cell component, is to use broad T cell-targeted immunosuppressive therapies. If DCs could be selectively targeted, the innate immune system could be repressed while the adaptive immune system was preserved. In effect, we could develop anti-inflammatory treatments that were not generally immunosuppressive. This DC-selective approach could lead to much safer outcomes, with considerably lower risk of infection and malignancy. For example, there are new treatments that specifically decrease the proposed monocytic DC precursors. Agents that target CX3CR1 are being developed, and are promising as an alternative approach to inhibit migration of the precursor cells into the skin, and hence prevent the development of the proposed causative DC. This information will provide a novel exciting and specific therapeutic strategy to prevent initiation and maintenance of psoriasis lesions, and this new knowledge could be explored in other skin diseases and autoimmune diseases.